Process for the preparation of 6-methyl-3-oxo-delta4, 6-steroids



United States Patent 3,117,966 PROCESS FQR THE PREPARATION OF6-METHYL-3-0X0-A -STEROIDS Vladimir Pen-ow, London, England, assignor toThe British Drug Houses Limited No Drawing. Filed Sept. 24, 1962, Ser.No. 225,966 Claims priority, application Great Britain Sept. 27, 1961 9Claims. (Cl. 260239.55)

This invention relates to a method for the preparation of6-methyl-3-oxo-A -steroids.

It is an object of the present invention to provide a new route to6-methyl-3-oxo-A -steroids employing as starting materials6-methylene-3-oxo-A -steroids.

6 methyl-3-oxo-4,6-dienic steroids are known to those skilled in the artas valuable compounds possessing biological activity. Thus, for example,l7u-ethynyl-l7fihydroxy-6-methylandrosta-4,6-dien-3-one is anorally-active progestational agent. 6-methyl-6-dehydroprogesterone hasprogestational and claudogenic activity.17aacetoxy-6-methylpregna-4,6-diene 3,20 dione and 170:,-awtoxy-S-methyl-l6rnethylenepregna 4,6 dime-3,20- dione (see Britishspecification No. 870,286 and Belgian Patent No. 594,445) andl7a-acetoxy-6,l6zx-dimethylpregna-4,6-diene-3,ZO-dione (see Britishspecification No. 884,544) are highly potent progestational agents andovulation inhibitors. 6-methyl-6-dehydrotestosterone has androgenicproperties. 6-methyl-6-dehydro cortisone acetate has glucocorticoidproperties.

According to the present invention there is provided a process for thepreparation of 6-methyl-3-oxo-A -steroids having, apart fromsubstituents and unsaturated linkages in rings A, B, C and D, thegeneral Formula I which process comprises contacting a6-methylene-3-oxou -steroid having, apart from substituents andunsaturated linkages in rings A, B, C and D, the general Formula Ii Me Iin a solvent with an activated metallic catalyst selected from the groupconsisting of palladium, platinum, rhodium, ruthenium, osmium, iridiumand nickel.

Palladium'is the preferred catalytic metal. Palladium-charcoal is thepreferred form of catalyst, but other forms such as palladium black,palladium/ calcium carbonate, palladium/barium carbonate and palladium/barium sulphate may also be employed.

Catalytic forms of platinum, rhodium, ruthenium, osmium and iridium suchas the forms in which the metal is dispersed onto charcoal, or Raneynickel, may likeice wise be used but, in general, are less suitable thanthe corresponding forms of palladium.

In the preferred embodiment of the invention activation of the preferredcatflyst, palladium charcoal, is achieved using ethanol, which alsofunctions as solvent.

The isomerisation proceeds best under neutral or slightly basicconditions. As the preferred catalyst (palladium charcoal) is oftenslightly acidic, it is preferred to add a small quantity of a Weaklybasic buffering salt to the isomerisation mixture. Sodium acetate isentirely satisfactory for this purpose, but other buffering salts mayequally well be employed.

The reaction is conveniently performed by heating the G-methylenesteroid (II) with approximately 20% by weight of 5% palladium charcoalin industrial spirit under reflux when isomerisation to the 6-methylsteroid (-1) occurs generally in from 12 to 60 hours. The quantity ofcatalyst employed is not critical as satisfactory conversion of (II) to(I) may be achieved using, for example, from 2% to 200% ofpalladium-charcoal allowing an appropriate length of time for thereaction to proceed to completion. The progress of the isomerisation mayreadily be followed by removing samples of the reaction mixture atregular intervals, filtering, and examining the filtrates by physicalmethods such as UV. absorption or The ultraviolet absorption spectrumfurnishes a particularly convenient parameter for this purpose as themaximum shifts from about 260 mu (for a. 6-.methylene- 3-oxo-A"=steroid)to about 288-289 mu (for a 6-methyl- 3-oxo-4,6-dienic steroid).

Alternatively the ethanol may be replaced by a lower primary orsecondary aliphatic alcohol and in particular by methanol, nori-propanol, nor i-butanol, ethylene glycol or its monoalkyl others,which may likewise be used to both activate the catalyst and function assolvent.

In another embodiment of the invention the catalyst is activated bycontact in a solvent with hydrogen or with an equivalent thereof.Elemental hydrogen is inconvenient on the industrial scale owing to itstendency to produce catalytic hydrogenation of both compounds (11) and(I), if present in excess of the amount required to activate thecatalyst. Equivalents of hydrogen, i.e. organic substances which readilydehydrogenate in the presence of the catalyst, are preferred. Thus, forexample, such organic substances as benzyl alcohol, cyclohexene,cyclohexadiene, phellandrene,4-phenyl-3,5-dicarbethoxy-2,6-dimethyl-1,4-dihydropyridh1e and manyother organic compounds as will be apparent to those skilled in the art,may be used to activate the catalyst. Thus, for example, conversion of(II) into (I) occurs following such procedures as:

Heating (H) with Pd-C in t-butanol under reflux in the presence of asmall quantity of cyclohexene; heating (II) with Pd-C in tetrahydrofuranor dioxan in the presence of a small quantity of cyclohexene; heating(II) with Pd-C in acetic acid in the presence of a small quantity ofbenzyl alcohol, or with slow or dropwise addition of benzyl alcohol;pretreating the PdC catalyst with hydrogen gas, in ethanol or anotherlower aliphatic alcohol, then adding (II) and heating the mixture underreflux.

When performing the preferred embodiment of the invention (PdC inethanol), the isomerisation reaction may be accelerated, if so desired,by adding to the reaction mixture such catalyst activators ascyclohexene and benzyl alcohol. Benzyl alcohol and cyclohexene are thepreferred accelerators.

Thus in yet another embodiment of the invention a dilute solution ofcyclohexene (for example, 1% solution u of cyclohexene in ethanol) isadded portionwise or continuously to the isomerisation mixturecomprising the 6-methylenic steroid (II) in, for example, ethanol underreflux, until isomerisation to (I) is complete. By using such conditionsthe quantity of catalyst employed may be reduced to 1 to 2% and the timeof isomerisation reduced to 1 to 4 hours.

The 6-methylene-3-oxo-A -steroids (H) which form the starting materialsof the present invention are described in our copending US. appln. Ser.Nos. 150,177, filed on November 6, 1961, and 176,423, filed on February28, 1962. Such 6-methylene-3-oxo-A -steroidal starting materials includecompounds of the androstane, 19-norandrostane, 9 3,la-androstane andpregnane, 19-norpregnane and 9B,10ot-pregnane series which mayadditionally contain further substituents as indicated below:

Hydroxyl groups.Hydroxyl groups and functional derivatives thereof inpositions 11, 12, 15, 16 (including 16-hydroxy methyl), 17, 18, 20 and21 (including the condensation products of 16cc,17a-glyCO1S withcarbonyl components).

Carbonyl gr0ups.Carbonyl groups at positions 11, 12, 16, 17, 18 and 20.

Carbalkoxy gr0ups.Carbalkoxy groups at C C and C or in a sidechain at CAllcyl groups.-Alkyl groups other than at C and C and in particularmethyl groups at C C C C and C21 and at C17.

Alkenyl gr0ups.Vinyl and allyl groups at C Methylene and erhylidenegroups.Such groups at positions 11, 16 and 17 and including the16a,17a-cyclomethylene group.

Lactone, ether and spiroketal residues.Spirolactone residues such asO.CO.CH .CH attached to C etheric groups at C and bridging C and Cspiroketal moieties such as are present in diosgenone, ketalisedcarbonyl groups.

Halogen gr0ups.Fluorine substituents in rings C and D or in thesidechain.

Unsaturated linkages.Unsaturated linkages at C 11 14, C16 and 17(20)-Ketol groups.Ketol groups at C -C C -C and C are preferably acylatedprior to reaction.

Corticoz'd sideclzain.The corticoid sidechain may be protected byacylation at C and at C and C by reaction with formaldehyde to give thebismethylenedioxy derivative, by forming the C C cyclic carbonate oracetonide or by other methods known to those skilled in the art, andsubsequently regenerated as desired.

Ep0xides.1n particular 1612:,170zand 95,115-epoxides.

In particular, the process of the invention may be applied to the6-methylenic derivatives of the following steroids and acyl derivativesthereof:

Testosterone Z-methyltestosterone 17a-methyltestosterone 9( 1 l-dehydro-17a-methyltestosterone 17a-hydroxyprogesterone 9 l 1-dehydro-17x-acyloxypro gesterone 16-methyl-17u-acyloxyprogesterone 9 11 -dehydro-16-methyl-17a-acyloxyprogesterone16-methylene-17a-acyloxyprogesterone 9 1 1-dehydro-16-methylene-17a-acyloxyprogesterone17a-hydroxy-1d-ethylideneprogesterone16a,17:x-dimethylmethylenedioxyprogesterone 9 1 1-dehydro-16a;171x-dimethylmethylenedioxyprogesterone Cortisone16-methylcortisone 21-methylcortisone 16-methylenecortisone 16OL-hYdXOXY cortisone and the 1 601,1702) -acetonide thereofHydrocortisone 1 6 -me-thylhydrocortisone 2 l-methylenehydrocortisone 16-methylenehydrocortisone 1 6u-hydroxyhydrocortisone and the 16 a, 170:)-acetonide thereof 17a,21-dihydroxypregna-4,9( 11)-diene-3 ,20-dione16-methyl-17a,21-dihydroxypregn-4,9(11)-diene-3,20-

dione 2l-methyl-17a,21-dihydroxypregna-4,9 1 1 -diene-3,20

dione 16-methylene-17u,21-dihydroxypregna-4,9 l 1 -diene- 3,20-dione16a-hydroxy-17u,21-dihydroxypregna-4,9( 11 )-diene- 3,20-dione and the(16,17) acetonide thereof 21-fiuoro-17a-hydroxypregna-4,9( 1 l-diene-3,20-dione and the (16,17) acetonide thereof 21-fluoro-17a-hydroxypregn-4-ene-3, 1 1,20-trione and the 16,17)acetonide thereof 21-fluoro-1 1,17a-dihydroxypregn-4-ene-3,20-dione andthe 616, 17 acetonide thereof 2 l-hydroxypregna-4, 17 -dien-3-one 11-oxo-21-hydroxypregna-4,l7-dien-3-one 1 1,21-dihydroxypregna-4,17-dien-3-one 9 1 1 -dehydro-2 1 -hydroxypregna-4, l 7-dien-3-0ne3-oxopregna-4, 17-dienoic acid (esters)3,11-di0xopregna-4,17-dien-21-oic acid (esters) 1 1-hydroxy-3-oxopregna-4, 17-dien-2 l-oic acid (esters) 9 l 1 -dehydro-3-oxopregna-4,17-dien-2 l-oic acid (esters) 2l-fluoro-17a-hydroxyprogesteroneProgesterone 16-methylprogesterone 1 la-hydroxyprogesterone 1l-oxoprogesterone 9 1 1 -dehydroprogesterone 2 l-methylprogesteroneDiosgenone l6-methyl-16,17-dehydroprogesterone 1 6-carbalkoxyprogesterone 16-hydroxymethylprogesterone v3-(3-oxo-17fi-hydroxyandrost-4-ene-17u-yl)propionic acid and lactone21-fiuoroprogesterone Testololactone The 9a-fiuoro-derivatives of thosecorticoids mentioned above 160:, 17a-cyclomethyleneprogesteroneFollowing is a description by way of example of methods for carrying theinvention into effect.

Example 1 17a-acetoxy-G-methyleneprogesterone (20 g.), sodium acetate(10 g.), 5% palladium charcoal (5 g.) and ethanol (200 ml.) were stirredand heated under reflux for 20 hours. A sample of the solution (0.5 ml.)was withdrawn and filtered. The filtrate showed an ultravioletabsorption maximum at 288.5 m indicating completion of the reaction. Thehot solution was filtered and the catalyst washed on the filter with hotethanol (50 ml.). The filtrate was diluted with hot water ml.) andallowed to cool. The crystalline product, purified from methanol, gave17ot-acetoxy-6-methylpregna-4,6-diene-3, 20 clione, needles, MP. 218 to220 C., [a] +5' (c, 0.85 in CHCl k 288 III/.0 (a 25,800) in ethanol.

Example 2 5 palladium-charcoal (100 mg.) was stirred and heated underreflux in ethanol (20 ml.) containing cyclohexene (0.2 ml.) for 2 hours.17a-acetoxy-6-methyleneprogesterone (1 g.) and sodium acetate (1 g.)were then added and stirring and heating were continued until a filteredsample of the solution exhibited an ultraviolet absorption maximum at288.5 my. (5 hours). The product, isolated as in Example 1 was17a-acetoxy-6-methylpregna-4,6-diene-3,20-dione, M.P. 218 to 220 C.

Example 3 5% palladium-charcoal (100 mg.) in ethanol (20 ml.) containingsodium acetate (0.5 g.) was stirred in hydrogen until absorption ceasedminutes ca. 10 ml. absorbed). The hydrogen atmosphere was replaced byair, and the mixture was stirred and heated under reflux for 5' minutesthen 17a-acetoxy-6-methyleneprogesterone (1 g.) was added. Afterstirring and heating for a further 6 hours the product was isolated asin Example 1, giving 17a-acetoxy-6-methylpregna-4,6-diene-3,20-dione,MP. 218 to 220 C.

Example 4 17oz-acetoxy-6-methylene progesterone (5 g.), 5%palladium-charcoal (100 mg), sodium acetate (5 g.) and ethanol (100 ml.)were heated under reflux and stirred while a 1% solution of cyclohexenein ethanol was added continuously at a uniform rate of 6 ml. per hour.After 1.5 hours a sample showed maximum ultraviolet absorption at 288.5m and the product was immediately isolated by the process of Example 1,giving 17a-acetoxy-6- methylpregna-4,6-diene-3,20-dione, M.P. 218 to 220C.

Example 5 5% palladium-charcoal (100 mg.) was stirred and heated underreflux in ethanol ml.) containing cyclohexene (0.2 ml.) for 2 hours.6-methylene-25D-spirest-4- en'3-one (1 g.) and sodium acetate were thenadded, and stirring and heating were continued for 5 hours. The hotsolution was filtered and the catalyst washed on the filter with hotethanol (50 ml.). The filtrate was diluted with water (150 ml.) and theproduct isolated with ether. Crystallisation from acetone-hexane gave6-methyl-25D- spirosta-4,6-dien-3-one in prisms, MP. 215 to 217 C. notdepressed in admixture with an authentic specimen.

Example 6 6-methylenepregn-4-en-3,20-dione (5 g.), 5% palladium charcoal100 mg), sodium acetate (5 g.) and ethanol (100 ml.) were heated underreflux and stirred while a 1% solution of cyclohexene in ethanol wasadded continuously at a uniform rate of 6 ml. per hour. After 1 /2hours, the solution was filtered and the product isolated with ether.Crystallisation from hexane gave 6-methylpregna-4,6-diene-3,20-dione,plates, Ml. 152154 C., [a] +69 (c. 1.01 in chloroform) Example 7 5%palladium-charcoal (200 mg.) in ethanol (50 ml.) containingsodiumacetate (1 g.) was stirred in hydrogen until absorption ceased. Thehydrogen atmosphere was replaced by air, and the mixture was stirred andheated under reflux for 5 minutes.17,8-acetoxy-6-methyleneandrost-4-en-3-one (2 g.) was added, and afterstirring and heating for a further 6 hours, the product was isolatedwith ether following removfl of the catalyst. Purification fromacetone-hexane gave l7B-acetoxy-6-methylandrosta-4,6-dien-3-one, plates,MP. 174 C., not depressed in admixture with an authentic specimen.

Example 8 170:,20:20,2l-bismethylenedioxy 6 methylenepregn-4-ene-3,11-dione (2 g.), sodium acetate (1 g.), 5% palladium-charcoal(0.5 g.) and ethanol (20 ml.) were stirred and heated under reflux for20 hours. The product, isolated as described in Example 1, wascrystallised to give 1711,20:20,21-bismethylenedioxy-6-methylpregna-4,6-diene-3,11-idone with A 291 m (log 6 4.36).

Example 9 6-methylene cortisone acetate (4 g.), sodium acetate (2 g.),5% palladium-charcoal (1 g.) and ethanol ml.) were stirred and heatedunder reflux for 18 hours. The product isolated as described in Example1, was crystallised to give 6-dehydro-6-methyl cortisone acetate, M.P.248 to 252 G, A 291 my (log e 4.37).

6 Example 10 Example 11 17,B-acetoxy-2a-methyl 6 methyleneandrost4-en-3- one (1 g.) in ethanol (20 ml.) was treated with 5%palladium-charcoal (50 mg.) and sodium acetate (1 g.). The mixture wasstirred and heated under reflux while a 1% solution of cyclohexene inethanol was added continuously at the rate of 6 ml. per hour. After twohours, the product was isolated as described in Example 1, and purifiedby crystallisation. l7fi-acetoxy-2a,6-dimethylandrosta-4,6-dien-3-onehad k 289 mp (log 6 4.37).

Example 12 l7a-acetoxy-6,l6-bisrnethylenepregn 4 ene-3,20-dione (2 g.),sodium acetate (1 g.), 5% palladium-charcoal (0.5 g.) and ethanol (20ml.) were stirred and heated under reflux for 20 hours. The product,isolated as described in Example 1, was crystallised to givel7a-aeetoxy- 6-methyl-16-methylenepregna-4,6-diene-3,20 di0ne, MP. 223to 225 C., identical in every respect with an authentic specimen.

Example 13 16-methy1l-6-methylene-16-dehydroprogesterone (1 g.), sodiumacetate (0.5 g.), 5% palladium-charcoal (0.25 g.) and ethanol (10 ml.)were stirred and heated under reflux for 16 hours. The product, isolatedas described in Example 1, was crystallised to give 6,16-dimethylpregna-4,6,16-triene-3,20-dione, having A 251 m (log 6 3.94) and 290 m (log 64.37).

Example 14 17a-acetoxy-16-ethylidene-6-methyleneprogesterone (2 g.),sodium acetate (1 g.), 5% palladium-charcoal (0.5 g.) and ethanol (20ml.) were stirred and heated under reflux for 20 hours. The product,isolated as described in Example 1, was crystallised to give17a-acetoxy-16- ethylidene 6-methylpregna-4,6-diene-3,20-dione having )t290 m (log 6 4.36).

Example 15 6 methylene 17B propionoxy-17a-(prop-1-ynyl)androst-4-en-3-one (0.5 g.), 5% palladium-charcoal (10 mg), sodiumacetate (0.5 g.) and ethanol (20 ml.) were heated under reflux andstirred while a 1% solution of cyclohexene in ethanol was addedcontinuously at a uniform rate of 6 ml. per hour. After 1 hour, theproduct was isolated and purified to give 6-methyl-17;8-propionoxy17o;-(prop l ynyl)-audrosta-4,6-dien-3-one having A 290 m (log 5 4.35).

Example 16 6 methyleneandrost 4-ene-3,l7-dione (1 g.), 5%palladium-charcoal (0.5 g.), sodium acetate (0.5 g.) and ethanol (10ml.) were stirred and heated under reflux for 28 hours. The catalyst wasremoved by filtration, and the filtrate diluted with water and extractedwith ether. The ether Was washed, dried and evaporated, and the productwas purified from acetone-hexane to give 6-methylandrosta-4,6-diene-3,17-dione, needles M.P. 163 to 164 C.,[(X]D25+1O6 (c. 0.66 in CHCl A 287 1,11. (e:22,300) in ethanol.

7 Example 17 17a-acetoxy-6-methyleneprogesterone (200 mg),platinum-charcoal (200 mg), sodium acetate (200 mg.) and ethanol (20ml.) were heated and stirred under reflux for 24 hours. The catalyst wasremoved by fir tration, and the product precipitated by the addition ofwater. Purification by chromatography on alumina (5 g.) gave 17aacetoxy-6-methylpregna-4,6-diene-3,20-dione, M.P. 218 to 220 C.

Example 18 17a-acetoxy-6-methyleneprogesterone (200 mg), 5%rhodium-charcoal (200 mg), sodium acetate (200 mg.) and ethanol (20 ml.)were heated and stirred under reflux for 96 hours. Chromatography of theproduct afforded 17oz acetoxy-6-methylpregna-4,6-diene-3,20-dione, k 288mp.

Example 19 Example 20 17,8 acetoxy 17a-methyl-6-methyleneandrost-4-en-3-0ne (1 g), sodium acetate (0.5 g.), 5% palladium-charcoal (0.25 g.)and ethanol ml.) were stirred and heated under reflux for 23 hours. Theproduct was isolated as described in Example 1 and purified bycrystallisation to give 17/3-acetoxy-6,17a-dirnethylandrosta-4,6-dien-3-one with A 290 mp (log 6 4.37).

Example 21 6 methylene-17B-propionoxy-l7a-vinylandrost-4-en-3- one (1g), 5% palladium-charcoal mg), sodium acetate (1 g.) and ethanol (20ml.) were heated under reflux and stirred while a 1% solution ofcyclohexene in ethanol was added continuously at a rate of 6 ml. perhour. After 1% hours, the product was isolated and purified to give6-methyl-17fl-propionoxy-17a-vinylandrosta- 4,6-dien-3-one having A 290m (log a 4.37).

Example 22 20B acetoxy 6-methylenepregn-4-en-3-one (2 g.), sodiumacetate (1 g.), 5% palladium-charcoal (0.5 g.) and ethanol (20 ml.) werestirred and heated under reflux for 18 hours. The product was isolatedas described in Example 1, and crystallised.20fi-acetoxy-6-methylpregna-4,6-dien-3-one with Amax, 290 my (log 64.36) was obtained.

Example 23 17a,20:20,21 bismethylenedioxy 11,3 hydroxy-6-methylenepregn-4-en-3-one (1 g.) was processed exactly as described inExample 22. The product was isolated and purified by crystallisation togive l7a,20:20,21-bismethylenedioxy11B-hydroxy-6-methylpregna-4,6-dien-3- one, having A 290 mp (log 64.36).

Example 24 17cc acetoxy 1Get-methyl-6-methylenepregn-4-ene- 3,20-dione(1 g.) was processed exactly as described in Example 22. The product wasisolated and crystallised from aqueous methanol, giving17a-acetoxy-6,16a-dimethylpregna-4,6-diene-3,20-dione, prisms, M.P. 202to 204 C., A 286 mp. (log 6 4.35).

Example 25 Treatment of 21-acetoxy-6-methylenepregu-4-ene-3,20- dione bythe process of Example 1 aiforded 2l-acetoxy- 86-rnethylpregna-4,6-diene-3,20-dione having A,,,,,,, 289 m (log 6 4.36).Y

Example 26 Treatment of17,8-hydroxy-17a-methyl-6-methyleneandrost-4-en-3-one by the process ofExample 1 gave 6,170:- dimethyl-17,8-hydroxyandrosta-4,6-dien-3-one,M.P. 157 to 158 G, A 290 mu (log 6 4.37).

Example 28 Treatment of 17a-acetoxy-2l-fluoro-6-methylenepregn-4-ene-3,20-dione by the process of Example 1 gave 170:- acetoxy 21-fluoro 6 methylpregna 4,6 diene 3,20-dione having A 290 m (log 5 4.36)

Example 29 The starting material employed in Example 29 was prepared asfollows:

16oc,17a cyclomethylene 6 formyl 3 methoxypregna-3,5-dien-20-one(British patent application No. 38,236/60) (2 g.) in a mixture ofmethanol (40 ml.) and tetrahydrofuran (50 ml.) was treated with sodiumborohydride (1 g), added in small portions over a period of 10 minutes.The mixture was set aside for 60 hours at room temperature, then pouredinto water and the product isolated with ether. Crystallisation fromacetone-hexane gave material with M.P. 114 C. A solution of thismaterial (1.5 g.) in acetic acid (10 ml.) was heated for 10 minutes atC., poured into water, and the product isolated with ether. Its solutionin pyridine (15 ml.) was added to chromium trioxide (1.5 g.) in pyridine15 m1.) and the mixture set aside overnight at room temperature. Ether(200 ml.) was added, and the mixture washed with dilute hydrochloricacid, then with aqueuos sodium hydrogen carbonate, water, and then driedover calcium chloride. The residue obtained on removal of the ether waspurified from acetone-hexane to give16a,l7a-cyclomethylene-6-methylenepregn-4- cue-3,20-dione, prisms, M.P.168 to 169 C.,

+362 (c., 0.83 in chloroform, A 260 m (e=l1,200).

Treatment of 16a,17a-cyclomethylene-G-methylenepregn-4-ene-3,20-dione bythe process of Example 22 gave 16a,17a cyclomethylene 6 nethylenepregna4,6 diene-3,20-dione, needles (from aqueous methanol), M.P. 138 to C.,[04 +177 (c., 1.1 in chloroform), A 289.5 my. (log e 4.38).

I claim:

1. A process for the preparation of a 6-methyl-3-oxo- A -steroid of theandrostane, 19-norandrostane, pregnane, and 19-norpregnane series, whichcomprises contaacting a corresponding 6-methylene-3-oxo-A steroid ofsaid series in a solvent in the presence of a weakly basic bufferingsalt with an activated metallic catalyst selected from the groupconsisting of palladium, platinum, rhodium, ruthenium, osmium, iridiumand nickel.

2. A process as claimed in claim 1 wherein palladium is the catalyticmetal employed in the form of palladiumcharcoal.

3. A process as claimed in claim 2 wherein a lower aliphatic alcohol isemployed as activator and solvent for the palladium-charcoal.

4. A process as claimed in claim 3 wherein the lower aliphatic alcoholis ethanol.

5. A process as claimed in claim 1 wherein the weakly basic bufferingsalt is sodium acetate.

6. A process as claimed in claim 1 wherein the 6- methylene steroid isheated with approximately 20% by weight or" 5% palladium-charcoal inethanol under reflux for from 12 to 60 hours.

' A process as claimed in claim 1 wherein the metallic catalyst isactivated by contact in a solvent with hydrogen.

8. A process as claimed in claim 7 wherein the metallic catalyst isactivated by contact in a solvent with a 5 plete.

small uantit of c clohexene.

10 9. A grocess as claimed in claim 8 wherein a 1% solution ofcyclohexene in ethanol is added continuous- 1' to the reaction mixturecomprising the 6-methylene steroid in ethanol under reflux untilisomerisation is com- No references cited.

1. A PROCESS FOR THE PREPARATION OF A 6-METHYL-3-OXO$4,6-STEROID OF THEANDROSTANE, 19-NORANDROSTANE, PREGNANE, AND 19-NORPREGNANE SERIES, WHICHCOMPRISES CONTACTING A CORRESPONDING 6-METHYLENE-3-OXO-$4 STEROID OFSAID SERIES IN A SOLVENT IN THE PRESENCE OF A WEAKLY BASIC BUFFERINGSALT WITH AN ACTIVATED METALLIC CATALYST SELECTED FROM THE GROUPCONSISTING OF PALLADIUM, PLATINUM, RHODIUM, RUTHENIUM, OSMIUM, IRRIDIUMAND NICKEL.